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Therapy Choices

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Non-Traditional Approaches: Hyperthermia, Hypoxia, Radiation & Ultrasound

Date: February 2, 2003

by Chaya Venkat

A Summary of Some Out-of-the-box Thinking

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There is considerable interest in the patient community in unusual approaches to treat or retard the growth of CLL. We will address some of these approaches that have shown some efficacy in published peer-reviewed research literature. There are, of course, many so-called therapies which we view with skepticism — see Questionable Therapies.

Low Dose Radiation Therapy for CLL

We don't often discuss radiation as a therapy modality these days, with reference to CLL. However, the article below says that as a way of dealing with localized lymph nodes, it might be worth a second look. The authors are careful to insist this is a "palliative" treatment, in other words they are aiming to reduce the lymph nodes size, and thereby the discomfort/pain that may be associated with them. The goal is not to achieve a complete response for the underlying CLL. 

Seven CLL patients were included in the study. Perhaps the full article has details of the patient group that is not here in the abstract. Out of the 7 patients, 5 responded to the low dose radiation, 2 patients had complete response, while 3 had partial response. It sounds like the treatments were well tolerated. For patients with large lymph nodes that are refractory to other modalities, this may be an option worth considering. 

I wonder why low dose radiation is less often discussed as a therapy options in the US, it is my impression that it is more often used in Europe. Any of you guys had radiation for enlarged lymph nodes? Care to share your experience with the rest of us?

News Report:

February 4, 2003

LYMPHOMA AND LEUKEMIA: Low-dose, local radiotherapy for palliation of cancerous masses very effective

According to recent research from Denmark, "indolent non-Hodgkin lymphoma (INHL) and chronic lymphocytic leukemia (CLL) are highly sensitive to radiotherapy (RT). Previous retrospective studies have shown high response rates after local palliative RT of 4 Gy in two fractions, which prompted this prospective Phase II trial of the palliative effect of this regimen in patients with disseminated INHL or CLL.

"Twenty-two patients (11 men, 11 women, median age 62 yrs, range 30- 89) with disseminated INHL (n=15) or CLL (n=7) were treated with local low dose RT, of 2 Gy X 2 within 3 days, with the aim of achieving palliation from localized lymphoma masses. The patients were treated a total of 31 different sites. Seventeen patients had previously been treated with chemotherapy. The median observation time after the start of RT was 8 months (range 3-26)," wrote J. Johannsson and colleagues, University of Copenhagen Hospital (Rigshosp). The researchers found that "all patients and all irradiated sites were assessable for response. Of the 22 patients, 18 responded to the treatment, corresponding to an overall response rate (RR) of 82%; 12 patients (55%) achieved a complete response (CR), 5 patients (22%) a partial response (PR), and 1 patient had a CR at three sites and a PR at one site. Of the 31 irradiated sites, 27 responded to treatment, corresponding to an overall RR of 87%; in 20 sites (65%) a CR was achieved, and in 7 sites (22%) a PR. Patients with disseminated INHL had an overall RR of 87% (74% CR, 13% PR); patients with CLL had an overall RR of 71% (29% CR, 42% PR). The median duration of response was estimated at 22 months. None of the patients had significant side effects from the treatment." 

The researchers concluded: "Low dose RT of 4 Gy in 2 fractions is a highly effective palliative treatment of localized lymphoma masses in patients with disseminated INHL and CLL. The treatment has minimal side effects." 

Johannsson and colleagues published their study in International Journal of Radiation Oncology Biology Physics (Phase II study of palliative low-dose local radiotherapy in disseminated indolent non- Hodgkin's lymphoma and chronic lymphocytic leukemia. Int J Radiat Oncol Biol Phys, 2002;54(5):1466-1470).  

For additional information, contact L. Specht, University of Copenhagen Hospital, Rigshosp, Finsen Center, Department Oncology 3994, 9 Blegdamsvej, DK-2100 Copenhagen, Denmark. 

To subscribe to the International Journal of Radiation Oncology Biology Physics, contact the publisher: Elsevier Science Inc., 360 Park Avenue South, New York, NY 10010-1710, USA. 

The information in this article comes under the major subject areas of Blood, Oncology, Non-Hodgkin Lymphoma and Radiotherapy.  

This article was prepared by Cancer Weekly editors from staff and other reports.

http://www.NewsRx.net

Of course, here we are talking about the therapeutic use of radiation, presumably carefully metered by the treating professionals to do more good than harm. But radiation is often used for diagnostic purposes, such as in X-rays and CT scans. It is fair to ask, how about the dangers of cumulative radiation exposure from diagnostic procedures? There have been recent articles that doctors are not really aware of or sensitized to the cumulative radiation exposure patients get as a result of various diagnostic tests. This is particularly true if you switch doctors or hospitals, each one wants his own tests run, and does not want to take the time to see if the information is already available in some other format from prior scans. They want the most detailed and best information available, it makes their treatment decisions that much easier. Good objective, but you as the patient need to be aware of the bigger picture.

Remember, with your compromised immune system, you are several times more likely to get secondary malignancies. Excessive exposure to radiation is a definite link to creation of new cancers. Levels that are tolerable in a healthy individual, because the immune surveillance is good and any incipient pre-cancer cell is effectively destroyed, may turn out to be dangerous to CLL patients.

I strongly urge you to maintain your own log of your radiation exposure levels, and insist that the technician tell you what the level is going to be, before the next test is done. It is sheer laziness on part of the medics if they are reluctant to look up and disclose this information. I think by law you are supposed to know and consent before you can be exposed to radiation. Talking to your oncologist about the type of scan that needs to be done,  weighing the risks and benefits, becomes much easier if you are armed with tabulated history of your prior exposures.

Hyperthermia and Hypoxia

There has been a buzz about hyperthermia for a while. PubMed gives literally hundreds of citations if you type in "hyperthermia" in their search engine. The link below is to a "lay person" article that gives some of the scoop, but I suspect it is from the perspective of the already converted believer. Anyhow, I have abstracted some of the quotes below from this article, for your reading pleasure.

Press Report:

Link: Hyperthermia

" Hyperthermia is heat treatment. The temperature of the tissue is elevated artificially with the aim of receiving therapeutic benefits. Hyperthermia is considered an adjunct to other treatments in this country, but has been recognized abroad as a stand-alone therapy as well, sometimes superior to chemo."

"One problem with treating cancer successfully is the fact that cancerous cells are very difficult to target specifically. In most respects, they are like normal cells, and even if they are not, they can hide the differences. But malignant cells are reliably more sensitive to heat than normal cells. Raising the temperature of the tumor is one way to selectively destroy cancer cells."

"Hyperthermia can be used by itself, and results in impressive shrinkage and even complete eradication (10-15%) of tumors. However, these results usually don't last, and the tumors re-grow. The synergistic effects of hyperthermia combined with radiation have been studied the most. Combined hyperthermia and radiation has been reported to yield higher complete and durable responses than radiation alone in superficial tumors."

"How hyperthermia works"

"Hyperthermia exerts its beneficial effect in several ways, according to the current understanding. Several studies have shown increased apoptosis in response to heat. Hyperthermia damages the membranes, cytoskeleton, and nucleus functions of malignant cells. It causes irreversible damage to cellular perspiration of these cells. Heat above 41 C also pushes cancer cells toward acidosis (decreased cellular pH) which decreases the cells' viability and transplantability."

"Hyperthermia activates the immune system. One source says: "Heat has a well known stimulatory effect on the immune system causing both increased production of interferon alpha, and increased immune surveillance." Another source mentions the release of lysosomes. Tumors have a tortuous growth of vessels feeding them blood, and these vessels are unable to dilate and dissipate heat as normal vessels do. So tumors take longer to heat, but then concentrate the heat within themselves."
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Here is a report from the well regarded British medical journal Lancet, that makes interesting reading.

Hyperthermia and its role in enhancing the effectiveness of radiotherapy and chemotherapy is now well accepted. There are several advanced clinical trials under way, but I have seen them only in reference to solid tumors, not hematological malignancies. I hope it is only a matter of time before drugs like Rituxan and Campath are combined with this non-toxic approach to enhancing efficacy of the drugs, without dose escalation. For example, Campath and Rituxan  both do a great job of cleaning out the CLL cells in peripheral blood, but they have a much harder time clearing out the lymph nodes and  bone marrow, especially if the tumor load is high. Can this barrier be overcome by combining these drugs with hyperthermia?

Folks, hyperthermia can be very dangerous if not administered carefully, under well controlled conditions. Heard of heat stroke? People can die from heat stroke in a short period of time.

There is a lot of information about hyperthermia in the medical literature, you can get a bunch of abstracts on PubMed by just typing in the word. I wish I kept the reference, but I read some where that the main reason hyperthermia is not more readily used in main stream cancer therapy is that it has to be monitored closely, and therefore very labor intensive, which makes it expensive (and unattractive).

Reference:

THE LANCET Oncology Vol 2 September 2001 524

Hyperthermia and hypoxia for cancer-cell destruction

This year has seen a burgeoning interest in a new approach to cancer therapy involving hyperthermia and hypoxia. At the American Society of Clinical Oncology meeting in San Francisco in May, Rolf Issels (University Hospital Medical Center Grosshadern, University of Munich, Germany) and colleagues presented some of the latest results from a 5-year phase II study of regional hyperthermia (RHT) combined with neoadjuvant chemotherapy in 59 patients with soft-tissue sarcoma. "Thirty-six patients were disease-free at the end of treatment and we now have the data to show that 5-year survival rate was 49%", reports Issels (Eur J Cancer, in press) The standard treatment – limb sparing surgery, followed by postoperative radiotherapy – gives an overall 5-year survival rate for high-risk patients of 15–35%.

"RHT seems to be potentiating the effect of the chemotherapy, but it was not possible to show exactly what contribution RHT made to the therapeutic outcome", adds Issels, "A randomised, phase III, multicentre European Organisation for Research and Treatment of Cancer (EORTC) study is currently underway to investigate this further – an interim report on 175 patients is expected in 2002".

There are three types of clinical hyperthermia: whole-body hyperthermia (WBH), in which radiant heat is used to induce systemic temperatures of 41°C; regional hyperthermia (RHT, Tmax 42°C), in which multiple microwave or ultrasound devices that deliver deep heat treatment are used to create an increase in temperature of up to 42oC in a reasonably large area around the tumour; and local hyperthermia (LHT), which is most commonly induced using a single microwave or ultrasound applicator.

The winning combination of hyperthermia and radiotherapy has been established in several phase III randomised studies in the USA and Europe, showing significant improvement in response and survival. Overall complete response rates for the two therapies combined are 70%; hyperthermia alone gives a 15% response, and radiotherapy alone about 35%. "This technique is particularly well defined in breast cancer, melanoma, head and neck tumours, cervical cancer, and glioblastoma," stresses Issels.

The relation between hyperthermia and chemotherapy is less well characterised. "Good progress is now being made in clinical trials, but these have been hindered until recently by the lack of adequate equipment for creating deep regional RHT and systemic heating", says Issels. "Many of the drugs used in chemotherapy – doxorubicin, cisplatin, carboplatin, melphalan, and methotrexate – all induce maximum cytotoxicity when the drug is given simultaneously with hyperthermia," agrees Giammaria Fiorentini (Department of Oncology, City Hospital of Ravenna, Italy), whose group has been experimenting with both hyperthermia and  hypoxia for over a decade.

The molecular mechanisms that underlie the success of hyperthermia in cancer therapy are not well understood. According to Fiorentini there are several theories to explain how the effect of melphalan is potentiated at higher body temperatures. "One is that hyperthermia causes a greater influx of melphalan into the cell, leading to higher intracellular drug accumulation. Another possibility is that at higher temperatures, melphalan is more adept at altering the quaternary structure of cellular DNA, favouring alkylation and so interrupting cell division. A third idea is that the drug plus hyperthermia may more easily induce cell arrest at the G2 phase of the cell cycle, through greater inhibition of protein kinase activity", he explains. The involvement of heat-shock proteins in the mechanism has also been mooted; in another recent study, Issels and others showed that hyperthermia may induce expression of heat-shock proteins such as HSP70 on tumours in vivo. "This may provide a danger signal to the immune system, recognised by dendritic cells and natural-killer cells, and promote a general antitumour response", he says.

Hypoxia in cancer treatment has become a hot topic since the observation that drugs like nitroimidazoles and mitomycins undergo bioreductive activation and become more toxic under hypoxic conditions. The mechanisms of action of several such compounds have now been widely studied and great efforts are being made to find new bioreductive agents. One is tirapazamine, a new class of hypoxia- selective cytotoxins. "Under hypoxic conditions, tirapazamine undergoes enzymatic reduction and forms a highly reactive radical. This can kill cells by causing DNA damage, which leads to chromosomal aberrations", explains Fiorentini. This hypoxia-induced ability to target cancer cells is independent of the P53 status of the cell. Fiorentini's group has gone one step  further by inducingmore hypoxia in an affected organ while giving a bioreductive drug specific to hypoxic cells. "We have been inducing acute hypoxia by blocking arterial flow with an angiographic occlusion catheter inflated in the hepatic artery and then giving a potent bioreductive agent such as mitomycin C intra-arterially", he says.

In one study, 27 patients with liver metastases were treated. Thirteen had complete necrosis of the metastases and nine had partial necrosis. "Taking advantage of `natural' hypoxia is useful, but carefully controlled induced hypoxia is clearly the way forward, particularly when the site of the tumour can be isolated", concludes Fiorentini.
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Ultrasound

This group of Belgian researchers presented an earlier paper on effect of Ultrasound on leukemic cells in ASH 2001. Below is an abstract of their more recent paper. Basically, they claim that low energy ultrasound kills leukemic cells, in a manner that is "smooth, specific and effective". 

To put things in perspective, the frequency of 1.8MHz is easily attained, as is the acoustical power they cite. In fact most of the wand type ultrasound equipment used in "sports medicine" to reduce muscle aches, etc. is in this range of frequency and power. 

If (and this is a big if), the concept works, one could visualize using ultrasound to shrink enlarged lymph nodes close to the surface. Or a leukapheresis type of procedure, where the blood is circulated through an ultrasound chamber. It sounds almost too good to be true, and over my life I have learnt to be suspicious of things that fall into that category. Let's keep an eye on this one, people, but don't go out and start massaging your nodes with ultrasound wands. You may want to look up other articles, on ultrasound and the combination of ultrasound with hyperthermia (increasing body temperature).

Abstract:

Exp Hematol 2002 Nov;30(11):1293-301

Ultrasonic low-energy treatment: a novel approach to induce apoptosis in human leukemic cells.

Lagneaux L, de Meulenaer EC, Delforge A, Dejeneffe M, Massy M, Moerman C, Hannecart B, Canivet Y, Lepeltier MF, Bron D. 

Laboratoire d'Hematologie Experimentale, Institut Jules Bordet, Universite Libre de Bruxelles, Brussels, Belgium. 

OBJECTIVE: We evaluated the cytotoxic effect of ultrasonic irradiation at low energy on the viability of normal and leukemic cells and the potential mechanisms of action inducing this cytotoxicity. 
MATERIALS AND METHODS: Human leukemia cell lines (K562, HL-60, KG1a, and Nalm-6), primary leukemic cells, and normal mononuclear cells are treated by ultrasound at a frequency of 1.8 MHz during various exposure times (acoustical power of 7 mW/mL) and immediately tested for cell viability by the trypan blue exclusion assay. Apoptosis is evaluated by cell morphology, phosphatidylserine exposure, and DNA fragmentation. The mitochondrial potential, glutathione content, caspase-3 activation, PARP cleavage, and bcl- 2/bax ratio are tested by flow cytometry. Cloning efficiency is evaluated by assays in methylcellulose. 
RESULTS: The technique we describe here, using minute amounts of energy and in the absence of any chemical synergy, specifically triggers apoptosis in leukemic cells while necrosis is significantly reduced. Ultrasonic treatment of 20 seconds' duration induces a series of successive phases showing the characteristic features of apoptosis: mitochondrial transmembrane potential disturbances, loss of phosphatidylserine asymmetry, morphological changes, and, finally, DNA fragmentation. In contrast to K562 cells, for which a significant reduction of cloning efficiency is observed, the growth of hematopoietic progenitors is totally unaffected. Ultrasound treatment is also associated with depletion of cellular glutathione content, suggesting a link with the oxidative stress. Moreover, the fact that active oxygen scavengers  reduce ultrasonic-induced apoptosis suggests a sonochemical mechanism.
CONCLUSION: The cell damage observed after exposure of leukemic cells to ultrasound is associated with the apoptotic process and may be a promising tool for a smooth, specific, and effective ex vivo purging of leukemic cells. 

PMID: 12423682
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